Cannabis use by individuals with, or at risk for, schizophrenia is increasingly recognized as a major public health concern. For example, cannabis use is linked to an increased risk for developing schizophrenia and poorer long-term outcomes in individuals who already have schizophrenia. Cannabis use also induces prefrontal cortex (PFC)-related cognitive impairments similar to those seen in schizophrenia. Interestingly, deficits in RFC GABA neurons may lead to cognitive problems in schizophrenia, and cannabis reduces GABA signaling by activating the CB1 receptor. Thus, one potential link between cannabis use and cognitive impairments in schizophrenia may involve an interaction of deficits in the RFC GABA system. Direct investigations of the eCB system in schizophrenia may help further clarify the biological basis for the negative consequences of cannabis use in schizophrenia. For example, determining whether the recently reported finding of lower RFC CB1 receptor levels in schizophrenia reflects a deficiency in eCB signaling, or, conversely, a downregulation of CB1 receptor levels in response to excessive eCB signaling requires knowledge of the eCB ligand (2-AG) that binds to the CB1 receptor. Furthermore, why is the eCB system altered in schizophrenia in the first place? One possibility is that alterations in eCB signaling in schizophrenia are pathogenetically downstream to impairments in GABA synthesis.Therefore, the first two aims will determine whether (and how) the mRNA and protein levels for the synthesizing and metabolizing enzymes (diacylglycerol lipase and monoglyceride lipase) for 2-AG are changed in the RFC in schizophrenia using quantitative PCR, in situ hybridization, Western blots, and immunocytochemistry. The third aim will use in vivo injections of lentiviral vectors expressing siRNA against the GABA synthesizing enzyme, GAD67, and determine the effects on markers of eCB signaling. The training goal of this application is to obtain the necessary research skills to become an independent investigator who tests pathogenetic hypotheses involving cortical circuitry abnormalities in schizophrenia by combining postmortem human brain tissue studies with cell-type specific genetic manipulations in animal models.